Prior to 1980, the most effective means of repairing diseased blood vessels was by surgery. A comprehensive review of the prior art of vascular surgery can be found in "Vascular Surgery" edited by Wesley S. Moore, Grune & Stratton, Inc. 1983. In one of the disclosed surgical procedures, a vascular graft (either biological or synthetic) is used to bypass the lesion to allow blood flow from the proximal to the distal end. Typically, in coronary artery repair procedures, an autogenous saphenous vein graft is used as a bypass graft to restore the normal blood flow in the heart. As surgical procedures of this kind are generally traumatic, requiring weeks of hospitalization and extensive surgical costs, alternative treatment methods have been sought. Percutaneous transluminal angioplasty (PTA) has since emerged to be the most popular method as the least traumatic interventional therapeutic approach for repairing atherosclerotic coronary and peripheral artery diseases in the past decade. There were approximately 300,000 angioplasty procedures for coronary artery diseases in the U.S. alone for 1988 (BBI Newsletter vol 13, No. 5, Table 4, Page 86, 1989). Despite the growth and acceptance of angioplasty, its overall success has been limited by vessel reclosures (abrupt reclosure and restenosis). Overall, vessel reclosure occurred in one third of cases over the past ten years. With the anticipated increase in angioplasty procedures in the coming years, a correspondingly greater number of patients will be affected as a result of vessel reclosure. The impact of vessel reclosure is therefore of major importance in terms of patient morbidity, repeat procedure risk, and increased health costs. It has been estimated that a reduction in the restenosis rate of 33% to 25% could save $300 million in overall healthcare costs. As such, an effective, reliable and safe method of reducing and perhaps preventing vessel reclosure is most welcome.
Many different approaches have been taken in an attempt to prevent post-angioplasty vessel reclosure. One such approach has been the use of an intravascular stent to mechanically keep the lumen open. One such stent is disclosed in U.S. Pat. No. 4,733,665, where an intravascular stent comprising of an expandable stainless steel wire mesh tube is used to prevent post angioplasty restenosis and vessel reclosure. The stent is positioned over an inflatable balloon secured to a catheter and is advanced to the stenosed region. The balloon is inflated, thereby expanding the stent into contact with the vessel wall. The elastic limit of the wire mesh is exceeded when the balloon is expanded, so that the stent retains its expanded configuration. U.S. Pat. No. 4,503,569 discloses a shape memory alloy stent which is advanced to a stenosed region on a catheter. The stent has the form of a coil spring. After the stent is in place, the stent is heated with a hot fluid causing the shape memory alloy to expand into contact with the blood vessel. Stents for blood vessel repair are also disclosed in U.S. Pat. Nos. 4,553,545 and 4,732,152. A plastic graft for repair of vascular system is disclosed in U.S. Pat. No. 4,740,207. U.S. Pat. No. 4,577,631 discloses a Dacron graft that is coated with an adhesive which may be activated by ultraviolet or ultrasonic energy after placement in the aorta. As most of these stents and grafts have been developed based on mechanical requirements, and are fabricated from metals, alloys, or plastics and remain in the blood vessel indefinitely, they generally have many disadvantages and limitations in fulfilling the requirements of an acceptable intravascular prosthesis which is in constant contact with the blood and is subjected to continuous pulsatile pressure in the body. The disadvantages of the prior art intravascular stents and grafts are discussed below.
Firstly, the selection of a blood compatible material is most critical in applications in contact with blood. Metals have high surface energy and are not blood compatible which may therefore induce acute thrombosis when implanted as an intraluminal or intravascular stent or graft. In addition, metals are non-resorbable and are subject to corrosion. Even the best stainless steel cannot be guaranteed that they will not corrode under the long term implantation conditions.
Secondly, compliance mismatch resulting in intimal hyperplasia and graft reclosure has been documented in many vascular grafting procedures. Metals are known to be non-compliant and it is not surprising that some chronic reclosure of the metal stent may be attributed to intimal hyperplasia formation. In fact, anastomotic hyperplasia as a result of compliance mismatch is still one of the major hurdles in developing a small diameter vessel for coronary bypass surgeries.
Furthermore, complete circumferential contact with the vessel endoluminal surface is critical for stent safety and efficacy. Incomplete expansion of the metal stent may be fatal. The continuous insult to the surrounding tissue due to pulsatile actions of the vessels may induce long term untoward effects. Moreover, metal stents have a fixed range of expansion within a blood vessel. In some cases the stent may be too small in diameter, even after expansion, to be affixed to the vessel wall, and in other cases, the stent may expand to such a diameter that the vessel is damaged or ruptured. In either case, improperly sized or positioned prior art stents require surgery for removal. The heat expandable metal, nitinol, has the additional disadvantage of incomplete expansion as a result of inadequate thermal exposure during deployment or from variabilities in stent material. Still further, migration of stents has been observed with prior art stents. Stent migration may be fatal. Stent migration may be due to under expansion, gradual change in metal properties, and the body's own defense to foreign material.
To circumvent some of the disadvantages of metal stents, Slepian, M. J. and Schindler, A. (Circulation, 78, Suppl IV: II-409, 1988) selected a synthetic polymeric material, linear aliphatic polyester for stent fabrication. This material is slowly degradable and has certain thermal properties that may be used to seal and pave the lumenal sites in situ. The investigators used a dual balloon deployment approach and melted the polymer in situ at 60.degree. C. followed by balloon compression directed flow of the melt polymer for vessel sealing and subsequently cooling the material to solidify the polymer seal or pave. This approach has been referred to as polymeric endoluminal paving and sealing (PEPS) in the prior art. This PEPS approach may have several potential disadvantages. The high temperature may have an unknown effect on the local tissue and cells. The melting and recrystallization within a vessel may not be a predictable event in such a life-sustaining process. Further, the long term effects of the degraded products are unknown. The adhesion of the polymer film with the tissue also increases the risk of fragmentation of the material which may cause potential embolization.
There are many advantages of using type I collagen material for intravascular stent or wound healing applications which can not be simulated by metals and synthetic polymers. Type I collagen molecule is a triple helix and has a unique protein configuration that is a coiled coil of three polypeptide chains or alpha chains. Two of the alpha chains are identical and are called alpha 1 chains and the third chain is slightly different in amino acid composition and is called alpha 2 chain. Each alpha chain twists in a left-handed helix with three residues per turn, and three chains are wound together in a right-handed superhelix to form a rod-like molecule about 1.4 nanometer in diameter and 300 nanometer long. The alpha chains each contain about 1,050 amino acid residues and the molecular weight of a type I collagen molecule is about 300,000 daltons. In each alpha chain within the triple helix every third amino acid residue is a glycine. Collagen is characterized by a high content of proline and hydroxyproline residues, the absence of tryptophane, a minor amount of aromatic amino acid, and a significant amount of dicarboxylic and dibasic amino residues. At both ends of the collagen molecule three are terminal peptide sequences known as telopeptides which are globular and are not triple helical in structure and which lack glycine at every third residue. These telopeptides are the primary sites of intermolecular crosslinking in the molecule. Some of the advantages of using type I collagen for the applications of the present invention are briefly summarized below.
Firstly, type I collagen is hypo-immunogenic. Antibodies against type I collagen molecule of one species cannot be raised in the second species without the use of Freund's Complete Adjuvant. The immunogenicity is reduced when collagen is in the fiber form. Chemical crosslinking further reduces the immunogenicity to a non-detectable level. In other words, purified type I collagen fibers are highly biocompatible.
Secondly, type I collagen is biodegradable and the rate of biodegradation can be controlled by chemical means such as by crosslinking with glutaraldehyde, formaldehyde or other bifunctional crosslinking agents. There are a number of cells (macrophages, polymorphonuclear leukocytes and fibroblasts) that, during wound healing, secrete the enzyme collagenases which cleave collagen at 1/4 position from the C-terminal end of the molecule. The two short triple-helices are not stable at body temperature and are denatured to random coiled peptides which are then degraded into amino acids and small peptides by proteases in the body. The amino acids and peptides are metabolized, presumably through the normal pathways similar to the resorption of host collagen during remodeling of the wound.
Further, type I collagen molecule has about 250 amino and guanidino groups (positively charged groups at pH 7.4) and about 250 carboxyl groups (negatively charged groups at pH 7.4). These side chain functional groups are reactive and can be modified by chemical means to change its physico-chemical, mechanical and biological properties. For example, native type I collagen fibers are thrombogenic. However, the thrombogenicity of the collagen can be significantly reduced when the collagen molecule is modified to a negatively charged protein.
Still further, type I collagen can be prepared either as a solution or as a highly swollen fibrillar dispersion such that medicaments in the form of small molecular drugs, peptides and macromolecules can be incorporated into the collagen fibers to form a composite material that would function as a vehicle for slow systemic release or as a local delivery system of the medicaments.
Repair of other tissues such as skin, nerve and meniscus cartilage has been attempted using type I collagen containing material. For example, Yannas et. al. fabricated an endodermal implant using collagen-glycosaminoglycan composite material (U.S. Pat. No. 4,060,081). Li used a semipermeable, resorbable type I collagen conduit for peripheral nerve repair (U.S. Pat. No. 4,963,146). Stone used biocompatible, resorbable type I collagen-glycosaminoglycan matrices to regenerate meniscus cartilage (U.S. Pat. No. 5,007,934).
A collagen wound healing matrix is disclosed in U.S. Pat. No. 5,024,841. This wound healing matrix is made from atelocollagen (pepsin solubilized skin collagen) and is not chemically crosslinked. As such, it does not possess the unique physico-chemical and mechanical properties that are critically required for the specific vascular applications of the present invention.
However, even with the various foregoing technologies which have been applied to repair damaged or diseased anatomical structures, a device successful as a vascular wound dressing and constructed from totally resorbable natural materials, or analogs thereof, has not been developed in the prior art.
Accordingly, it is an object of the present invention to provide improved vascular wound healing devices, which provide structural support to the damaged or diseased vessel segment, allowing normal blood flow.
It is another object of the present invention to provide vascular wound dressings which are biocompatible, bioresorbable, hemocompatible, and compliant.
It is a further object of the present invention to provide vascular wound dressing devices which when released at the selective sites inside a blood vessel will self expand to adhere to the vessel wall via hydration of the material.
It is a yet another object of the present invention to provide a means to deliver medicaments to the selective sites either intravascularly or extravascularly for therapeutic applications.
It is still another object of the present invention to provide a means to manufacture the vascular wound dressings.
It is yet a further object of the present invention to provide a means to repair the damaged or diseased blood vessel.